A significant relationship exists between iron nutrition and cognition and behavior. Behavioral problems are also observed in children with high manganese and manganese neurotoxicity resulting in a Parkinson-like disorder that is widely recognized in workers employed in mining and manganese ore processing. Our recent work has established that iron deficiency enhances olfactory uptake of manganese and promotes accumulation of this toxic metal in the basal ganglia. Thus, the major underlying hypothesis of this proposal is that absorption of inhaled manganese is up-regulated upon iron-deficiency such that neurological complications of poor iron status are compounded by an increased vulnerability to the toxic effects of manganese exposure. The proposed research will contribute fundamental understanding of physiological risks associated with metal-induced toxicity and, more specifically, the interactions between iron status and manganese neurotoxicity. To accomplish this goal we will: 1) Determine the distribution of intranasally instilled manganese in the brain of control and iron-deficient rats using magnetic resonance imaging;2) Determine motor coordination and learning/memory capacity of exposed and non-exposed cohorts through use of rotorod and bridge-walking as well Morris water maze tests;and 3) Examine CNS damage due to manganese intoxication in control and iron-deficient rats by determining indices of oxidative stress (3- nitrotyrosine and 8-hydroxy-2'deoxyguanosine levels), identifying neuronal degeneration (Fluoro-Jade staining) and evaluating astrocyte viability using anti-fibrillary acidic protein (GFAP) and microglia status using anti-isolectin B4.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Humble, Michael C
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Harvard University
Schools of Public Health
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Rodan, Lance H; Hauptman, Marissa; D'Gama, Alissa M et al. (2018) Novel founder intronic variant in SLC39A14 in two families causing Manganism and potential treatment strategies. Mol Genet Metab 124:161-167
Thompson, Khristy J; Hein, Jennifer; Baez, Andrew et al. (2018) Manganese transport and toxicity in polarized WIF-B hepatocytes. Am J Physiol Gastrointest Liver Physiol 315:G351-G363
Seo, Young Ah; Elkhader, Jamal A; Wessling-Resnick, Marianne (2016) Distribution of manganese and other biometals in flatiron mice. Biometals 29:147-55
Seo, Young Ah; Wessling-Resnick, Marianne (2015) Ferroportin deficiency impairs manganese metabolism in flatiron mice. FASEB J 29:2726-33
Wessling-Resnick, Marianne (2015) Nramp1 and Other Transporters Involved in Metal Withholding during Infection. J Biol Chem 290:18984-90
Kim, Jonghan; Wessling-Resnick, Marianne (2014) Iron and mechanisms of emotional behavior. J Nutr Biochem 25:1101-1107
Veuthey, Tania; Hoffmann, Dana; Vaidya, Vishal S et al. (2014) Impaired renal function and development in Belgrade rats. Am J Physiol Renal Physiol 306:F333-43
Seo, Young Ah; Li, Yuan; Wessling-Resnick, Marianne (2013) Iron depletion increases manganese uptake and potentiates apoptosis through ER stress. Neurotoxicology 38:67-73
Kim, Jonghan; Buckett, Peter D; Wessling-Resnick, Marianne (2013) Absorption of manganese and iron in a mouse model of hemochromatosis. PLoS One 8:e64944
Kim, Jonghan; Jia, Xuming; Buckett, Peter D et al. (2013) Iron loading impairs lipoprotein lipase activity and promotes hypertriglyceridemia. FASEB J 27:1657-63

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